The therapeutic use of neuroleptics in schizophrenia and other disorders can result in the development of an iatrogenic disease commonly called tardive dyskinesia. This serious side effect of neuroleptic therapy is generally believed to result, at least in part, from a supersensitive dopamine receptor in the basal ganglia. Supersensitivity in dopamine receptor function has been demonstrated in animals following chronic neuroleptic administration to rats. A systematic analysis of both the behavior (stereotypy) and biochemical (ligand-binding) alterations induced by the neuroleptics, and on the modulation of their development by drugs and hormones will yield information on the neurochemical factors that contribute to the development of this disease. Also the study of these parameters in a new animal model which displays a chronic and perhaps permanent supersensitivity to dopamine will add to our understanding of the long-term neurochemical alterations induced by the underlying pathophysiology and perhaps yield insight into possible treatment paradigms for this chronic dsease. In particular, this grant deals with a new approach, that of down regulation of the dopamine receptors (desensitization) by endogenous substances. Estrogens appear to have this property. By studying the mechanisms of action of estrogen on the down regulation of dopamine receptors we hope to gain new insight into possible new therapeutic treatments for tardive dyskinesia.